Benzimidazole nucleosides are particularly attractive as potential antiviral agents because of their ability to avoid some major pathways of bioactive purine (bicyclic) nucleoside inactivation, e.g., deamination by adenosine deaminase and glycosidic bond cleavage by purine nucleoside phosphorylases. However, known benzimidazole nucleosides such as 5,6-dichloro-1-(.beta.-D-ribofuranosyl) benzimidazole (DRB) have demonstrated only marginal levels of activity or generally unacceptable levels of cytotoxicity, or both, thereby greatly diminishing their usefulness in the treatment of viral infections.
A number of benzimidazole nucleosides have been synthesized and tested for their antiviral activity and cytotoxicity in an effort to identify a compound with superior anti-human cytomegalovirus (HCMV) activity to ganciclovir and foscarnet. Antiviral activity of polysubstituted benzimidazoles such as 5,6-dichloro-1 -(.beta.-D-ribofuranosyl) benzimidazole (DRB) and some closely related derivatives have been previously described (I. Tamm, Science (1954) Vol. 120:847-848). Their activity against specific viruses, such as RNA rhinovirus and DNA herpes simplex virus type 1 and type 2, also has been reported.
Several of the ribofuranosyl benzimidazole analogs, including 2,5,6-trichloro-1 -(.beta.-D-ribofuranosyl)benzimidazole (TCRB) have shown very potent activity against HCMV and low cellular toxicity at concentrations inhibiting viral growth. Structural activity relationships of TCRB and heterocycle and carbohydrate modified derivatives have been reported. (See, Revankar, G. R. and Townsend, L. B. (1968) J. Heterocyclic Chem. Vol. 5:477-483; Townsend, L. B. and Drach, J. C., Fifth International Conference on Antiviral Research Vancouver, British Columbia, March 1992; Revankar, G. R. and Townsend, L. B. (1968) J. Heterocyclic Chem. Vol. 5:615-620; Zou, R. et al. "Design, synthesis and antiviral evaluation of some TCRB analogs modified on the benzene moiety," Poster #142, Division of Medicinal Chemistry, 204th American Chemical Society National Meeting, Washington, D. C., Aug. 23-28, 1992; and Saluja, S. et al. "Synthesis and antiviral activity of certain 2-substituted-5,6-dichlorobenzimidazole acyclic nucleosides," Poster #146, Division of Medicinal Chemistry, 204th American Chemical Society National Meeting, Washington, D. C., Aug. 23-28, 1992.) A number of substituted benzimidazoles have also been described in U.S. Pat. No. 5,248,672 and U.S. Pat. No. 5,360,795. These disclosures, however, do not disclose the structure or synthesis of the compounds which are the subject of this invention.
Some modifications of the heterocycle have given analogs that are significantly more active than TCRB. However, most of these analogs are also more cytotoxic than TCRB, resulting in compounds with a little improved therapeutic index. Attempts to modify the carbohydrate moiety, by replacing the ribose with arabinose, xylose or acyclic analogues have given compounds less active than TCRB. Somewhat surprisingly a 5'-deoxy-.beta.-D-ribofuranosyl derivative of TCRB, 2,5,6-trichloro-1-(5'-deoxy-.beta.-D-ribofuranosyl) benzimidazole, was shown to be about 10 times more active than TCRB and have a better therapeutic index than TCRB. However, no other 5'-modified derivatives, other than 2-bromo and 2-chloro analogs disclosed in U.S. Pat. No. 5,360,795, have been reported to date.